bioRxiv : the preprint server for biology · 2026
Metabolic Rewiring at the Pyruvate Node Drives Severe Pneumonia and T-Cell Suppression in Serotype 3 Streptococcus pneumoniae Infection.
СтатьяПрепринтНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Takeshita Kenichi, Vidal Ana G Jop, Vidal Jorge E
Аннотация
BACKGROUND: Serotype 3 (ST3) Streptococcus pneumoniae remains a major cause of invasive pneumococcal disease and pneumonia despite PCV13 introduction, in part due to potent immune evasion properties. The contribution of the pyruvate metabolic node (SpxB/LctO pathways) to ST3 pathogenesis is poorly defined.
METHODS: We investigated oxygen-dependent fitness, virulence, and lung pathology in the ST3 strain WU2 and isogenic ΔspxB, ΔlctO, and ΔspxBΔlctO mutants. In vitro growth was assessed under nasopharyngeal (21% O2) and alveolar (14% O2) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology (H&E, confocal microscopy), and lung transcriptomics (RNA-seq).
RESULTS: ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O2, alleviated by spxB deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused high mortality with severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation. The ΔspxB mutant accelerated lethality with enhanced distal lung damage, uncontrolled dissemination, and amplified inflammation. Wild-type infection uniquely induced targeted reorganization of bronchial epithelial membranes, forming prominent bacterium-laden blebs-host-derived membrane protrusions encapsulating intact pneumococci. These novel structures facilitated organized bacterial translocation into tissue without overt cytotoxicity and were largely absent in spxB-deficient mutants despite comparable lung burdens. RNA-seq analysis revealed SpxB-dependent suppression of T cell activation (e.g., Rag1 and Themis) and acute inflammatory pathways, consistent with immune sequestration via blebs.
CONCLUSIONS: The SpxB-dependent pathway orchestrates ST3 virulence by enabling metabolic adaptation and driving bleb-mediated epithelial invasion and immune evasion in the lung. These bacterium-laden blebs represent a novel hallmark mechanism in pneumococcal pathogenesis, offering new insights and potential therapeutic targets.
METHODS: We investigated oxygen-dependent fitness, virulence, and lung pathology in the ST3 strain WU2 and isogenic ΔspxB, ΔlctO, and ΔspxBΔlctO mutants. In vitro growth was assessed under nasopharyngeal (21% O2) and alveolar (14% O2) conditions. Murine pneumonia models evaluated survival, bacterial burdens, histopathology (H&E, confocal microscopy), and lung transcriptomics (RNA-seq).
RESULTS: ST3-strain exhibited a unique oxygen-sensitive growth defect at 21% O2, alleviated by spxB deletion, indicating metabolic burden from pyruvate flux. In mice, wild-type WU2 caused high mortality with severe suppurative bronchopneumonia, alveolar consolidation, hemorrhage, and perivascular inflammation. The ΔspxB mutant accelerated lethality with enhanced distal lung damage, uncontrolled dissemination, and amplified inflammation. Wild-type infection uniquely induced targeted reorganization of bronchial epithelial membranes, forming prominent bacterium-laden blebs-host-derived membrane protrusions encapsulating intact pneumococci. These novel structures facilitated organized bacterial translocation into tissue without overt cytotoxicity and were largely absent in spxB-deficient mutants despite comparable lung burdens. RNA-seq analysis revealed SpxB-dependent suppression of T cell activation (e.g., Rag1 and Themis) and acute inflammatory pathways, consistent with immune sequestration via blebs.
CONCLUSIONS: The SpxB-dependent pathway orchestrates ST3 virulence by enabling metabolic adaptation and driving bleb-mediated epithelial invasion and immune evasion in the lung. These bacterium-laden blebs represent a novel hallmark mechanism in pneumococcal pathogenesis, offering new insights and potential therapeutic targets.